The ubiquitin conjugation system is a posttranslational modification system. By the function of three kinds of enzymes, a ubiquitin activating enzyme (E1), a ubiquitin conjugating enzyme (E2) and a ubiquitin ligase (E3), the ubiquitin system conjugates polyubiquitin chains, polymer of ubiquitin, to substrate proteins selectively recognized by E3s and regulates their functions. Although it was originally considered that all polyubiquitinated proteins are led to degradation, the concept of polyubiquitination has been broadened and it is currently understood that polyubiquitination regulates protein functions in various manners. Various polyubiquitin chains with different linkage of ubiquitins are present in the living body, and it is being proved that the regulatory mechanism for polyubiquitinated proteins varies with the kind of the polyubiquitin chain. It has been conventionally considered that polyubiquitin chains are assembled by formation of isopeptide bonds via lysine residues of ubiquitins. In such circumstances, the present inventor is the first in the world to show assembly of a linear polyubiquitin chain via N-terminal methionine, and involvement of the linear polyubiquitination in NF-κB activation.
Specifically, the present inventor found out that a complex of HOIL-1L and HOIP is a ubiquitin ligase which mediates assembly of a linear polyubiquitin chain, and named the complex LUBAC (linear ubiquitin chain assemble complex) (see Non Patent Literature 1). Further, the present inventor clarified that the LUBAC ubiquitin ligase is involved in the classical pathway of NF-κB activation in that the LUBAC ubiquitin ligase mediates linear ubiquitination of NEMO (NF-κB essential modulator), a component of the IKK (IκB kinase) complex, which leads to IKK activation and selective activation of NF-κB (see Non Patent Literature 2).
Furthermore, the present inventor found out that Sharpin is also a constituent of the ubiquitin ligase for mediating assembly of a linear polyubiquitin chain. Accordingly, the present inventor decided to refer to, as LUBAC, a ubiquitin ligase complex composed of the three proteins, namely Sharpin, HOIL-1L and HOIP, or composed of two proteins, namely HOIL-1L and HOIP, or Sharpin and HOIP. Regarding Sharpin, it is reported that mice with spontaneous mutation of Sharpin, which are called cpdm mice, present with immune system disorders and the like including chronic dermatitis and absence of Peyer's patches (see Non Patent Literature 3).